In a recent issue of Cell Death and Differentiation, Ko and colleagues investigated how the genetic inhibition of autophagy would impact on the response of human and murine lung carcinoma cells to radiation therapy, in vitro and in vivo. 26 In line with previous reports, these authors observed that cancer cells stably depleted of essential autophagic factors such as ATG5 and Beclin 1 are more sensitive to the cytostatic/cytotoxic effects of ionizing irradiation than their wild-type counterparts, in vitro. Along similar lines, autophagy-deficient cancer cells growing in immunodeficient hosts exhibited an improved response to radiation therapy as compared with autophagy-proficient cells of the same type. 26 These findings confirm that autophagy limits the efficacy of ionizing irradiation in settings in which therapeutic responses rely for the most part on cancer cell-intrinsic mechanisms. Importantly, the response to radiotherapy of autophagy-incompetent tumors growing in syngeneic immunocompetent mice was decreased as compared with that of autophagycompetent neoplasms. 26 In this setting, the pharmacological inhibition of extracellular nucleotidases (artificially increasing the pericellular concentration of ATP) restored the radiosensitivity of autophagydeficient cancers, hence facilitating tumor infiltration by lymphocytes. Thus, in scenarios in which radiotherapy exerts antineoplastic effects mostly through the activation of tumor-specific immune responses, autophagy mediates a beneficial, rather than detrimental, function. Altogether, these observations indicate that in immunocompetent hosts, cancer cell-extrinsic, immunological mechanisms may contribute to the therapeutic efficacy of ionizing irradiation more significantly than cancer cell-intrinsic ones. In this setting, the use of pharmacological inhibitors of autophagy as a strategy to sensitize cancer cells to therapy may not be justified. Conversely, the combination of ionizing irradiation with agents that stimulate the autophagic flux and/or with immunostimulatory interventions might yield optimal therapeutic responses. Further investigation is required to address this hypothesis in detail.